Authors: James Forrester
The Heart Healers (40 page)
THE GREATEST DISCOVERIES
in medicine are those that force us to rethink our beliefs about disease and our role in managing it. Let’s see how this applies to our new understanding of atherogenesis (plaque formation) and your own cardiac health. For those of us without symptoms, we want to reduce the amount of cholesterol entering the blood vessel wall and accelerate its egress. In people with CAD we need to keep stable plaques from becoming vulnerable plaques. For those with ruptured plaques, like my dad, we need to stabilize them. This understanding of atherogenesis allows us to develop a realistic strategy for preventing heart attack and sudden death in each of us, instead of reacting after it happens. Our journey has brought us to that pivotal stage in medicine, where understanding cause precedes cure, where CAD becomes a preventable disease.
Central to the prevention of CAD and its complications in my own life, and possibly yours, is the statin class of drugs. The story of statins, the most important in the history of cardiology, teaches us more about the incredible twists and turns of scientific research and discovery than any other in our half-century chronicle. At the end you will shake your head and say, “Is that really how it happened?”
Not all chemicals are bad. Without chemicals such as hydrogen and oxygen, for example, there would be no way to make water, a vital ingredient in beer.
—DAVE BARRY, PULITZER PRIZE–WINNING AMERICAN AUTHOR AND JOURNALIST
AS RUSSELL ROSS
was beginning his research on formation of cholesterol plaques, halfway around the world Japanese biochemist Akira Endo was beginning a search for a way to inhibit cholesterol synthesis. About two-thirds of the cholesterol in our body is made in the liver, the rest enters through our intestines after we eat. Endo’s dream was that he might discover a drug that would lower blood cholesterol, bringing both profit and fame to his employer, Japan’s Sankyo pharmaceutical company.
Endo was the son of a farming family from the snowy far north of Japan’s Honshu Island. As a child he had been taught about nature by his grandfather. One plant that fascinated both of them was a fungus that was poisonous to flies, but had no toxic effect on people. This inconsequential childhood experience would play a central role in the rest of Endo’s adult life.
Years later as a young chemist hired by the Sankyo, Endo first distinguished himself by discovering an enzyme that removed natural contaminants from wine and cider. Sankyo rewarded his commercially valuable research with a year of sabbatical study in the United States at a place of his choosing. Endo chose the lipid metabolism laboratory in New York’s Albert Einstein Medical College, the home of renowned coronary bypass surgeon Robert Goetz. Endo arrived in New York City just as it became the hub of the new internal mammary artery bypass surgery for CAD. Seeing the juxtaposition of bypass surgery while working in a lab devoted to the study of blood cholesterol metabolism inspired him: he would find a drug that blocked cholesterol synthesis.
Recalling his childhood in Honshu, Endo had a hunch. Knowing that fungi produced substances that killed invaders, he hypothesized that they did so by inhibiting the manufacture of cholesterol, which is essential for the formation of cell membranes in most species on the evolutionary ladder from bacteria to humans. Although fungi had acquired a distinctly negative reputation in modern times, from destruction of vineyards, to poisonous mushrooms, to insistently infecting dark crannies of the human body, Endo believed that mankind’s lowly pest might also carry a silver bullet, an inhibitor of cholesterol synthesis.
Endo planned his hunt. His project was stunning in its potential for both boredom and failure, calling for a commitment to dogged persistence that recalls John Gibbon and his heart-lung machine. He would make extracts of fungi, then measure the effect of each extract on the synthesis of cholesterol by rat liver cells. If the first fungal extract had no effect, he would test the next, continuing until he found one that worked. His strategy was neither new, nor proven by prior discovery. In the 1970s the National Cancer Institute had blindly thrown drug after drug at cultures of malignant cells, searching for a cure for cancer, with stunningly little success. Endo’s blind-ended research project was a pharmaceutical misfit, yet each day Endo arrived in the Sankyo lab near a south Tokyo train station like Sisyphus to push his metaphorical rock back up the hill, “doing grunt work every day until we got sick of it.”
At least he was efficient. He ramped up his testing regimen to a capacity of ten new fungal extracts each day. As negative results piled up day after day, many of us would have despaired. But to Endo each day’s experiment was a new quest. After all, no man steps in the same river twice, since the river is not same and neither is the man. In the next two and a half years Endo tested 6,392 fungal extracts. Two years of his life had produced, well, two compounds that inhibited cholesterol synthesis. Just two. Both lurked in a remote and unlikely landscape: a fungus that infected the Japanese Mikan orange. But unknown Akira Endo had made the century’s critical breakthrough in CAD prevention. While searching for a needle in the haystack Akira Endo had discovered the farmer’s daughter. He had discovered a member of the statin drug family, the wonder drug for treatment of CAD.
That the future savior of millions of CAD patient lives might be a pest that infected an orange is curious. Even curiouser was that the fungus that produced the two statins was a member of the penicillium genus. Yes that penicillium. Endo’s statin was produced by a mold called penicillium citrium. The source of penicillin, the wonder drug antibiotic, was its cousin penicillium notatum. By quelling infection, penicillin had ended the reign of infection as mankind’s leading cause of death, allowing CAD to become the new number one killer. Statins are penicillin for the heart, and will soon dislodge heart disease as the number one killer. Endo chose one of the compounds to pursue further. He called it mevastatin.
Endo’s research style reflected his own postwar society. Quiet, patient, deliberate. He would cross the stream by feeling each rock in turn, each step determined by his experience with his prior step. His next step was to identify how mevastatin lowered cholesterol. He found that it worked by inhibiting the most critical step in the synthesis of cholesterol. In an era when political revolutions were occurring violently in public squares, a scientific revolution had begun quietly in a cubbyhole within a laboratory next to a train station.
Mevastatin was an elusive participant. To isolate a paltry 23 milligrams of the drug, he had to plow through 600 liters of fungus extract. But still those 23 milligrams might be cardiology’s Holy Grail, the bookend to Russell Ross’s cause, the way to prevent CAD.
His next step would be the proof. Endo could hardly control his excitement as he tried his drug in laboratory rats. Unknown at that time, blood cholesterol in rats exists predominantly in the form of HDL (good cholesterol). Statins are specific inhibitors of LDL (bad cholesterol) synthesis, with little effect on HDL. He was thunderstruck when the drug had little effect on the rat’s total blood cholesterol.
Discouraged, Endo was baffled about where to turn. Just as everyone had predicted, he had invested his life in a project with a dead end.
It was time to visit the local bar. One night a fellow research scientist offered him some chickens he had used for research and was about to sacrifice. Endo could test his drug in another species. Who knows, maybe hens are different from rats. Endo took the offer, and mevastatin lived another day. The hens’ cholesterol fell by 50%.
Back on track, he extended his studies to monkeys. Their blood cholesterol promptly fell by 20 to 35%. Endo was thrilled. Sankyo patented mevastatin in 1974 and Endo published his results in 1976. Endo presented his data the same year at the International Symposium on Drugs Affecting Lipid Metabolism in Philadelphia. His report drew little interest from attendees at the symposium. Sankyo executives, confirmed in their skeptical view of Endo’s research, and convinced that a blood cholesterol lowering drug would have no important market, deemed Endo’s discovery unworthy of further investment. In 1970s Japan, when a boss told an employee to stop, he stopped. No discussion was necessary. Told to quit and without funding, mevastatin and Endo teetered on pharmaceutical oblivion.
But Endo thought differently. Like Werner Forssmann and his catheter in 1929 Germany, Endo accepted his superiors’ verdict and yet pursued his own instinct. At Osaka University, four hours’ drive away, he knew that Dr. Akira Yamamoto had a cohort of patients with inherited elevated cholesterol level, a rare condition called familial hypercholesterolemia. Yamamoto, with no effective therapy for elevated cholesterol, was delighted to try Endo’s compound. Endo got the drug to him. With no idea about what might be an appropriate or inappropriate dose in a human, Yamamoto gave the drug to an eighteen-year-old girl. She promptly developed the most common side effect of statins, muscle weakness. Yamamoto’s superiors ordered him to discontinue drug testing. Endo had driven up another blind alley.
But here chance intervened. Yamamoto was as mavericky as Endo. He reduced the dose and secretly tried again in other patients. Yamamoto stared in astonishment as one blood chemistry slip after another piled up on his desk. He was looking at eighty-point drops in blood cholesterol in his patients, an average reduction of 22 to 35%. This astonishing outcome was the largest reduction in blood cholesterol ever recorded. Yamamoto excitedly told Endo that he had found a substance like none he had ever seen before. In today’s regulated research environment we cringe at every step in this out-of-control scenario, which would unquestionably result in termination of both investigators and legal proceedings against the pharmaceutical company and clinic for lack of institutional control. Yet Endo had succeeded by listening to his own counsel.
Endo took Yamamoto’s results to his bosses at Sankyo. How could they deny such promising results? Suppressing their outrage at Endo’s insubordination, and anxious to save face, the bosses reversed course. They agreed to initiate a clinical trial. Endo had cleared his last hurdle. Patience and persistence. Patience had shown him the path to success; persistence had carried him there. If the clinical trial confirmed Yamamoto’s results, and he of course believed it would, his dream would become a reality.
Shortly after beginning the trial, the bosses called him into the office. They would continue the trial but Endo did not fit the Sankyo mold. His career at Sankyo was finished. On a bleak December day in 1978, with his fellow workers forbidden to assist him, Akira Endo lugged boxes filled with the shards of his shattered dream to a waiting truck.
Endo had chosen the path less taken, only to discover, like many iconoclasts before him, that it led to a dead end. If Endo wanted to continue his research, it would have to be at Tokyo Noko Agricultural University. But his bosses had decreed that Endo’s work on mevastatin would proceed no further; indeed his discovery would never be developed as a drug.
* * *
ENDO’S DISCOVERY OF
statins and its subsequent abandonment bears a striking parallel to the fascinating story of its moldy cousin penicillin. On September 3, 1928, Scottish chemist Alexander Fleming returned to his laboratory at St. Mary’s Hospital from a vacation at his country house. Always untidy, before leaving Fleming had stacked his discarded petri dishes with cultures of staphylococcus bacteria in a corner of the lab for cleaning on his return. As Fleming picked up the long-ignored cultures, he saw that some cultures had circular patches of dead bacteria, with a contaminating fungus in the center.
Fleming reveled in chance discovery. Six years earlier he had chanced upon a similar discovery when his nose inadvertently dripped onto the petri dish. The bacteria died, leading Fleming to discover lysozyme, a natural bacterial inhibitor in human tears and nasal fluid. The discovery proved that a substance capable of killing bacteria could be nontoxic in humans. In the ensuing six years, Fleming had set out to find a practical wonder drug that would have the same effect. He had not found one but now, recalling his prior experience, Fleming decided to investigate further.
Fleming grew the fungus in pure culture, and determined that it was a member of the penicillium genus. The mold turned out to be an airborne contaminant that wafted up from the lab of a mold expert conducting studies on the floor below him. Calling his extract “mold juice,” Fleming conducted experiments on cultures of a number of bacteria known to cause infections in humans. He discovered that the juice killed the bacteria that caused scarlet fever, pneumonia, meningitis, and diphtheria. Like Endo, he had discovered a wonder drug. But like Endo, he suffered a similar fate. His publication the following year in the
British Journal of Experimental Pathology
generated little interest in the scientific community.
Fleming persisted, year after year. But he was poorly equipped to carry his discovery further. He had difficulty cultivating the mold, and had even more trouble extracting its antibiotic product. After ten years of searching without success for a collaborator who could isolate a clinically usable penicillin, he abandoned his quest, and moved on to different research. But Europe was now in the second year of World War II, and young men were dying across the battlefields of Europe from minor wounds that blossomed into blood-borne infection throughout the body. Desperate for a wartime antibiotic, the British and U.S. governments authorized funds for discovery of a wonder drug. At Oxford, Australian Howard Florey and his German-Jewish immigrant trainee Ernst Chain took a second look at Fleming’s failed discovery. Within a year they had devised a method for purifying and concentrating penicillin by controlling the pH of the mold juice and then freeze-drying it.
